Neuronal malfunction and damage may be induced by toxic, aggregation-prone proteins and a number of neurological disorders are characterized by such conditions. These include disorders such as amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, prion disease, polyglutamine expansion disease, spinocerebellar ataxia, spinal and bulbar muscular atrophy, spongiform encephalopathy, tauopathy, Huntington's disease or dystonia.
Toxic, aggregation-prone proteins that cause such diseases and genes encoding the proteins have been identified. Normal metabolic enzymes recycle proteins creating a perpetual cycle of synthesis and degradation. Mutation in these genes results in abnormal accumulation and degradation of misfolded proteins. These misfolded proteins are known to result in neuronal inclusions and plaques which may be indicative of neuronal damage. Therefore, the understanding of cellular mechanisms and the identification of molecular tools required for the reduction, inhibition and amelioration of such misfolded proteins are critical. Furthermore, an understanding of the effects of protein misfolding and aggregation on neuronal survival will allow the development of rational, effective treatment for these disorders.
Alzheimer's disease, the most common form of dementia, is a neurodegenerative disorder caused by damage of neurons and synapses due to abnormal aggregation of β-amyloids and tau proteins that have existed normally in the brain, leading to formation of amyloid plaques (Aβ plaques) and neurofibrillary tangles, respectively.
Alzheimer's disease is the third cause of age-related deaths, followed by cerebrovascular disease and cancer. The disease is known for placing a great burden on caregivers including psychological, economic and social aspects because the mean duration of the disease is over 10 years.
β-Amyloids, specifically found in the brains of Alzheimer patients are peptides generated by metabolism by secretases. They occur as monomers, oligomers, profibrils, fibrils or plaques depending on the progress of the disease. Among them, the oligomers and profibrils exhibiting active dynamic variation are known as the main cause that damages the brain cells.
Clinical trials revealed that abnormal aggregation of β-amyloids occurs in the brain 10-15 years prior to the onset of the symptoms of Alzheimer's disease (Perrin R J, Fagan A M, Holtzman D M. “Multimodal techniques for diagnosis and prognosis of Alzheimer's disease.” Nature. 2009; 461: 916-22). Since the β-amyloid can be transported across the blood-brain barrier (BBB) by RAGEs and LRPs present in the BBB, in the form of small monomers, dimers or trimers, the change in β-amyloid concentration in blood may be directly associated with the progress of Alzheimer's disease.
There are opposing opinions about diagnosis of Alzheimer's disease based on the β-amyloid concentration in blood. There are reports that β-amyloid is increased with the progress of Alzheimer's disease (van Oijen M, Hofman A, Soares H D, Koudstaal P J, Breteler M M. “Plasma Abeta(1-40) and Abeta(1-42) and the risk of dementia: a prospective case-cohort study.” Lancet Neurol. 2006; 8:655-660, Mayeux R, Honig L S, Tang M X, Manly J, Stern Y, Schupf N, Mehta P D. “Plasma A[beta]40 and A[beta]42 and Alzheimer's disease: relation to age, mortality, and risk.” Neurology. 2003; 8: 1185-1190), whereas there are opposing reports that β-amyloid in blood decreases with the progress of Alzheimer's disease (Sundstrom J, Ingelsson E, Ronnemaa E, Arnlov J, Gunnarsson M D, Hyman B T, Basun H. et al. “Plasma beta amyloid and the risk of Alzheimer disease and dementia in elderly men: a prospective, population-based cohort study.” Arch Neurol. 2008; 8: 256-263). Furthermore, there are reports that the change in β-amyloid in blood is unrelated with the decline in cognitive ability due to Alzheimer's disease (Hansson O, Zetterberg H, Vanmechelen E, Vanderstichele H, Andreasson U, Londos E, Wallin A, Minthon L, Blennow K. “Evaluation of plasma Abeta(40) and Abeta(42) as predictors of conversion to Alzheimer's disease in patients with mild cognitive impairment.” Neurobiol Aging. 2010; 8: 357-367, Lopez O L, Kuller L H, Mehta P D, Becker J T, Gach H M, Sweet R A, Chang Y F, Tracy R, DeKosky S T. “Plasma amyloid levels and the risk of AD in normal subjects in the cardiovascular health study.” Neurology. 2008; 8: 1664-1671). The discrepancies in study results seem to be caused by the fact that it is difficult to accurately determine the level of β-amyloids in blood.
At present, a definitive diagnosis of Alzheimer's disease can be made only through autopsy after death. Although its progress can be diagnosed by indirect examination of symptoms based on physical, neurological or physiological examination, measurement of β-amyloid in the cerebrospinal fluid and, most accurately, monitoring of structural and functional change of the brain and identification of β-amyloid plaques through brain imaging, they are very invasive and cost a lot. Because of these disadvantages, it is difficult to accurately diagnose Alzheimer's disease.